Disability threatens the independence of many older adults and results in substantial late-life health care needs and associated expenditures. Sarcopenia, defined as loss of muscle mass and strength, plays a central role in disability. Our long-term goals are to gain insight into the processes that underlie the development of sarcopenia and disability and to identify possible strategies for interventions that reduce the ris of sarcopenia and disability. In the first two cycles of this R01, we examined the hypothesis that oxidative stress contributes to loss of muscle strength, decline in physical performance, disability, and mortality in older adults, and our findings support this paradigm. We also showed that advanced glycation end products (AGEs) and receptor for AGEs (RAGE) were independently associated with poor muscle strength, disability, and mortality. In the third cycle, we propose to examine the relationship between the anti-aging hormone klotho and sarcopenia in older adults. Klotho is a recently discovered hormone that plays a role in suppressing oxidative stress and is implicated in the pathogenesis of sarcopenia. We hypothesize that adults with low serum klotho levels have (1) lower skeletal muscle mass and strength and slower walking speed, and (2) greater decline of skeletal muscle mass and strength and walking speed, and (3) higher risk of mobility limitation, disability, and death. To address these hypotheses, we will study the relationship between serum klotho concentrations and the above outcomes in 2734 adults in the Health, Aging, and Body Composition (Health ABC) Study, a community-based prospective study of aging. We will measure serum klotho at baseline and examine the relationship between serum klotho and skeletal muscle mass, muscle strength, walking speed, mobility limitation, disability, and mortality over follow-up. Our propose studies will expand the knowledge of klotho into a novel area of investigation that focuses on sarcopenia and aging in community-dwelling adults. PUBLIC HEALTH RELEVANCE: This project is relevant to public health as it aims to characterize the relationship between klotho, a recently discovered hormone, with decline of muscle mass, muscle strength, physical performance, disability, and mortality in older US adults.